https://doi.org/10.1007/s00392-025-02625-4
1Universitätsklinikum Bonn Medizinische Klinik und Poliklinik II Bonn, Deutschland; 2Department of Internal Medicine, Section Pharmacology and Vascular Medicine, Erasmus University Medical Center Rotterdam, Niederlande; 3Department of Neuroscience, Biomedical Research Institute, European Graduate School of Neuroscience, Hasselt University Hasselt, Belgien; 4Universitätsklinikum Bonn Institut für Klinische Chemie und Klinische Pharmakologie Bonn, Deutschland
Background:
The liver X receptor beta (LXRβ) is one of the central regulators of cellular cholesterol metabolism and there is suggestive evidence for its association with aortic valve stenosis (AS). Long neglected due to undesired side effects, saringosterol is the first reasonable agonist for LXRβ. However, its influence on AS has not yet been sufficiently elucidated.
Methods:
To study the effect of saringosterol on cellular cholesterol metabolism, we stimulated human valvular interstitial cells (VIC) with saringosterol under procalcifying conditions. The expression of the cholesterol transporters ABCA1 and ABCG1 was measured by real-time PCR, as well as ACTA-2 and RUNX-2 for adverse cell differentiation.
In vivo, mice were treated with saringosterol at a dose equivalent to that in cell culture or a control diet. Hepatic, bile and plasma sterol concentrations were measured using gas chromatography-mass spectrometry with selected ion monitoring. Expression of LXRβ-regulated genes in tissue samples was analysed using qPCR. Aortic valve stenosis was examined in a wire-injury model and quantified using echocardiography and subsequent histology.
In addition, aortic valve tissue samples from patients with AS were compared with tissue from patients with aortic regurgitation using transcriptome analysis.
Results:
In vitro, stimulation with saringosterol led to a significant, dose-dependent induction of ABCA1 and ABCG1, which could be completely reversed by the LXR antagonist GSK2033. In contrast, saringosterol significantly reduced the expression of the markers for osteoblastic differentiation, RUNX-2, and for myofibroblastic differentiation, ACTA-2.
In vivo, oral administration of saringosterol led to an accumulation in the liver and to increased plasma levels of saringosterol. Subsequently, there was increased gene expression of LXR targets in the liver and intestine. At the same time, adverse side effects such as steatosis hepatis could be ruled out.
Six weeks after wire-injury, aortic valve peak velocity increased. This effect was attenuated in mice receiving saringosterol (saringosterol vs. vehicle: 1867 ± 112.6 mm/s vs. 2246 ± 118.1 mm/s; n = 10-11; p < 0.05). This finding was accompanied by a reduction in valve area by H.E.-staining (saringosterol vs. vehicle: 0.119 ± 0.013 mm2 vs. 0.163 ± 0.011 mm2; n = 10–11; p < 0.05).
In human samples, we were able to show that various GO terms related to LXRb like GO:0046890 - regulation of lipid biosynthetic process (Score 1.91; p.adjust = 0.031; p-value were differentially regulated.
Conclusion:
In this study, we were able to show that stimulation with saringosterol improved cellular cholesterol efflux in VIC and simultaneously reduced adverse cell differentiation. In vivo, oral administration of saringosterol is efficacious and safe. It effectively induced LXRb targets and ameliorated induced aortic valve stenosis. Transcriptome analysis indicated a central role for LXRb in human aortic valve stenosis.